This is the first competing renewal application of the Vanderbilt-Ingram Cancer Center (VICC) Breast Cancer SPORE Grant. It is comprised of investigators with expertise in cellular signaling and molecular biology, breast pathology, medical, surgical, and radiation oncology, clinical trial design, epidemiology and population studies, mass spectrometry, imaging, biostatistics, and biomedical informatics. We have made progress in our previous funding cycle, have established productive collaborations with other SPOREs and other national and international groups, and have firmly established a true multidisciplinary program which we believe will be productive in the years to come. In this competing renewal we propose four bi-directional translational projects addressing basic, clinical and population research questions in human breast cancer. Project 1: Resistance to antiestrogen therapy in hormone receptor-positive breast cancer (Carlos L. Arteaga, MD) Project 2: p63/p73 signaling axis as a target for treatment of triple negative breast cancer (Jennifer Pietenpol, PhD) Project 3: Cellular mechanisms of bone quality in metastatic breast cancer (Gregory Mundy, MD) Project 4: Genetic predictors of progression of premalignant breast disease (Jeffrey Smith, MD, PhD and William Dupont, PhD) In our opinion, these projects meet the eligibility criteria set forth in the SPORE guidelines. They span themes involving discovery of mechanisms of antiestrogen resistance, determining pathogenic mechanisms and new therapies for triple negative breast cancer, identifying genetic markers of breast cancer risk in women with preneoplastic mammary lesions, and investigating mechanisms and biomarkers of bone quality in patients with metastatic breast cancer. The SPORE has access to a substantial breast cancer population and an established record of accrual to clinical trials. The leadership of the VICC and VUMC has provided strong Institutional support for the success of the individuals involved in this application. A significant amount of support has been promised by the Institution in the event of successful funding of this application. Meritorious research applications for developmental (pilot) projects will be solicited from throughout the VICC, VUMC, and Meharry Medical College. The SPORE has supported and will continue to identify and support the careers of young investigators starting a career in breast cancer and of more established investigators adding a promising domain in breast cancer research to their programs. To support the research aims in the translational research projects, we propose five shared Core Resources. Each of these cores supports at least 3 projects in this competing renewal application. They are Administration &Outreach, Tissue, Clinical, Biostatistics, and Imaging Cores.